Common variable immunodeficiency (CVID) is a clinical diagnosis given to patients who suffer with an unexplained deficiencies of serum immunoglobulins. The presenting complaint for most CVID patients is recurrent sinopulmonary infections. Recent work suggests that a reduction in the memory B cell compartment may be a key feature in the pathogenesis of the disease, especially among patients with loss of function mutations in the genes that encode ICOS or TACI, both of which are factors involved in promoting the long term survival of antigen-responsive B cells and their immunoglobulin-secreting, plasma cell progeny. However, among our clinic population of CVID patients in the Southeastern US, the greatest genetic linkage is to the major histocompatibility complex (MHC) on chromosome 6, with almost half inheriting HLA*B44. We recently characterized a separate group of patients within our clinic population who presented with adult-onset recurrent sinopulmonary infections (RESPI) and serum immunoglobulin levels above the threshold for diagnosis with CVID. The prevalence of HLA*B44 in this population proved similar to that in CVID. Recognition of patients who fit into the RESPI category among first and second degree relatives of CVID patients led us to the hypothesis that these RESPI patients are suffering from the effects of the same genetic susceptibility to immune dysfunction that manifests more severely in classic CVID. With no obvious link as yet between HLA*B44 and neighboring genes to a common ICOS or TACI pathway, the extent of correlation between reduced B cell numbers and MHC-associated RESPI and CVID remains unclear. In the present application, we propose to test whether memory B cell numbers are reduced in HLA*B44-associated CVID and RESPI. If so, then this would support use of memory B cell determinations in the clinical evaluation of patients with unexplained recurrent sinopulmonary infection. We further propose to use this information to help map the putative common susceptibility gene for RESPI/CVID. Characterization of a gene or genes within the MHC that can be used to predict susceptibility to RESPI and alter memory B cell numbers could help define and extend the spectrum of what is already the most common primary immune deficiency under the care of clinical immunologists in the US. Identification of a susceptibility gene would help to elucidate the mechanism(s) that underlie susceptibility to infection, facilitate diagnosis, and point to new avenues for prevention and treatment. PUBLIC HEALTH RELEVANCE: One current hypothesis holds that common variable immune deficiency (CVID) reflects an inability to produce or maintain memory B cells. In our clinic, almost one-half of our CVID patients, as well as almost one-half of patients with normal serum antibody levels and repeated infections of the lungs and sinuses (RESPI), have inherited HLA*B44, suggesting linkage between this MHC allele and susceptibility to infection. We propose to use these patient populations to test whether the patients with infections in spite of normal serum immunoglobulin levels also have low memory B cell numbers and to identify the susceptibility gene linked to HLA*B44, which should help elucidate the mechanism behind this susceptibility to infections.